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Population Pharmacokinetics and Pharmacodynamics of the Neutralizing Antibodies Bamlanivimab and Etesevimab in Patients With Mild to Moderate COVID‐19 Infection
Author(s) -
Chigutsa Emmanuel,
O’Brien Lisa,
FergusonSells Lisa,
Long Amanda,
Chien Jenny
Publication year - 2021
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.2420
Subject(s) - pharmacokinetics , medicine , viral load , pharmacodynamics , placebo , population , confidence interval , antibody , drug , pharmacology , immunology , virus , pathology , alternative medicine , environmental health
Bamlanivimab and etesevimab are neutralizing antibodies indicated for treatment of coronavirus disease 2019 (COVID‐19) in patients with early mild or moderate disease. We present the use of pharmacokinetic/pharmacodynamic (PK/PD) modeling that characterizes the timecourse of viral load obtained from 2,970 patients from 2 phase II clinical trials. The model was used for identification of optimal doses that would result in at least 90% of patients achieving serum drug concentrations that result in 90% of maximum drug effect (IC90) for at least 28 days. The serum IC90 (95% confidence interval) was estimated to be 4.2 (3.2–4.3) µg/mL for bamlanivimab and 12.6 (9.7–12.8) µg/mL for etesevimab. Observed clinical trial data confirmed PK and PK/PD model predictions that doses of 700 mg bamlanivimab and 1,400 mg etesevimab would result in maximum reduction in viral load, with no additional effect seen at higher doses. No dose adjustment is recommended as age, sex, race, baseline viral load, and hepatic impairment did not have a significant impact on the PK of the antibodies. Earlier drug administration resulted in greater reductions in viral load, demonstrating the importance of receiving treatment as soon as possible. Relative to placebo, typical reduction in viral load over a 7‐day period was estimated to be 80 or 93% (drug administered 4 days or 1 day after the onset of symptoms, respectively), P < 0.0001. PK/PD modeling and simulation was pivotal throughout the drug development and emergency use authorization process.